Parametric release is defined as the system of release that gives the assurance that the product is of the intended quality based on information collected during the manufacturing process and on the compliance with specific GMP requirements related to Parametric Release.

All medicines must comply with the requirements stated in the specifications. Does it mean all the tests as stated in the specifications are to be carried out prior to release of the finished product? The answer is NO! This is where the concept of parametric release is introduced. Parametric release is used as an operational alternative to routine release testing of certain, specific parameters.

Parametric release is based on the evaluation of the data generated during process validation and review of the continuous monitoring data generated during routine operations. The principles of parametric release may be applied during the stages of manufacture of different products resulting in the elimination of certain, specific tests of the finished product. However,

This often leads to following issues:

  1. Delay in patient access to critical/ life-saving drug products
  2. Blockage of valuable space in the warehouse
  3. Increased cost of expenditure due to high cost sterility testing
  4. False positive results may further lead to unnecessary investigations and holding of batches
  5. Blockage of financial resources of the manufacturer

Parametric release is normally used for elimination of routine sterility testing for terminally sterilized drug products. Concept of parametric release may also be extended to reduction or elimination of other finished product testing also.

Parametric release of sterile drug products:

Sterility testing is a mandatory test as per various pharmacopoeias for the testing and subsequent release of sterile drug products. This sterility testing requires the product to be stored for a minimum incubation period of 14 days to allow for possible microbial growth in samples before obtaining results from this test. During this period, the finished product is to be kept on hold in the designated area of Warehouse.

Additionally, sterility testing by cultivation has following limitations w.r.t. detection of contamination:

  1. The small sampling size of test lots restricts the ability to capture those microorganisms dispersed in a large volume,
  2. The limited ability of the prescribed culture media to stimulate growth of all potential microorganisms

Parametric release is defined as a sterility assurance release program where demonstrated control of the sterilization process enables a firm to use defined critical process controls, in lieu of the sterility test. This may be further explained as the release of terminally sterilized batches or lots of sterile products based upon compliance with the defined critical parameters of sterilization without having to perform the requirements as stated under Sterility Tests of any pharmacopoeia.

Under this strategy, market release of terminally sterilized products can be based upon meeting the defined sterilization parameters and not on performing an approved sterility test. Meeting the requirements of the parametric release process can provide greater assurance that a batch meets the sterility requirement than can be achieved with a sterility test of finished units drawn from the batch. The release of each batch is dependent on the successful demonstration that predetermined, validated sterilizing conditions have been achieved throughout the load. All relevant sterilization parameters e.g. temperature, pressure and time, must be accurately controlled and measured.

Parametric release is possible only when:

  1. There is an in-depth knowledge of the process, product and mode of sterilization,
  2. The physical parameters of processing are well defined, predictable, and measurable, and;
  3. The lethality of the cycle has been microbiologically validated through the use of appropriate biological indicators or, in the case of ionizing radiation, the appropriate microbiological and dosimetric tests.

As explained above, sterility tests are marred with numerous limitations. Hence, once a sterilization process is fully validated and operates consistently, a combination of physical sterilization data such as accumulated lethality or dosimetry in combination with other methods, such as load monitors (e.g., biological indicators, thermochemical indicators, or physicochemical integrators), can provide more accurate information than the sterility test regarding the release of terminally sterilized products.

Four modes of sterilization that qualifies for parametric release are:

  1. Moist Heat
  2. Dry Heat
  3. Ethylene Oxide (recommended only in USP, Ph.Eur. does not include it for parametric release)
  4. Ionizing radiation

Parametric release can only be applied to products terminally sterilized in their final containers as they represent the lowest risk category of sterile pharmaceutical products. Unlike products aseptically manufactured in a microbiologically controlled environment, terminally sterilized products are subjected to a sterilization process that imparts a measurable minimum sterility assurance level, or SAL. Because aseptic processing relies on exclusion of microbiological contamination and is not based upon lethality imparted on the product in its sealed container, it is not possible to estimate the SAL. In case of aseptic processing, SAL can only be estimated from media fill contamination rates or other forms of risk assessment.

In the case of terminal sterilization, it is possible to calculate a minimum SAL or Probability of Nonsterility (PNS) quite accurately. The terms PNS and SAL are often used interchangeably. Terminally sterilized products must have a probability of non-sterility (PNS) of not more than one in a million units produced.

Validation of sterilization procedure: The strategies used to validate a terminal sterilization process development fall into three categories:

  1. Bioburden-based process.
  2. Biological indicator/bioburden combined process.
  3. Overkill process.

Parametric release first requires that the chosen sterilization process be designed and validated to achieve a 10–6 PNS. Validation of sterilization processes mostly includes the validation of physical parameters of the process and of its microbiological effectiveness through the use of biological indicators. Widely recognized biological indicator organisms shall be used in the validation of moist heat processes because they provide a means of comparing physically measured lethality data with biological lethality. There should be a reasonable correlation between physically measured lethality data (F0) and biological lethality as determined by the evaluation of the process with biological indicators.

The predictable effectiveness of bioburden-based terminal sterilization is based on the number and resistance of microorganisms on or in a product. For this reason, one component of parametric release is an active microbiology control program to monitor the count and sterilization resistance of product bioburden. Bioburden control and enumeration is of far less significance when the overkill process design is used. In many cases, overkill processes do not require extensive ongoing assessment of bioburden and require less in-process control of the manufacturing environment.

Parametric release shall be done only after regulatory approval. The regulatory decision is based on assessment of the dossier submitted. Demonstrated reliability of the production terminal sterilization cycle, microbiological control, and monitoring and control of production cycle parameters within established validated limits are part of this assessment. Approval of a parametric release program is dependent on the ability to demonstrate successful and reproducible execution of the specific terminal sterilization cycle for the drug product using the container closure system(s), production load configuration(s), and production sterilizer(s) at the location(s) proposed for commercial production. A risk assessment statement consistent with the principles of ICH Q9 (ICH 2006) should be provided that describes the following:

A. Control Strategy for the Terminal Sterilization Program: This is to ensure that the acceptance criteria of the parametric release process and terminal sterilization cycle are met in order to ensure product sterility. It includes:

  1. The rationale for the methods implemented to monitor and control the terminal sterilization process used for the product release (the critical process parameters);
  2. The rationale for the selection of critical process parameter(s);
  3. A description of the acceptance criteria for parametric release;
  4. A description of the drug product and container closure system (including secondary packaging, as applicable) that will be part of the parametric release program;
  5. A description of the proposed production loading patterns and verification that they are within the validated limits for the terminal sterilization cycle, or a statement that they have not changed since last approved and validated (as applicable); and
  6. A description of the microbiological monitoring plan for the product and components prior to terminal sterilization or a statement that the plan has not changed since last validated. Spore detection and heat resistance studies should be emphasized for bioburden-based sterilization cycles.

 

B. Risk Assessment, Process Understanding, and Prior Knowledge: For parametric release reliability of the control strategy of the sterility assurance program is of prime importance. Accordingly, the risk assessment should include:

  1. Consistency of performance of the terminal sterilization cycle within the validated limits;
  2. Factors leading to risk for the sterility of the product namely terminal sterilization cycle, loading patterns, the container closure system (including secondary packaging), and any potential contamination risks from the environment (as appropriate). Disciplines of Hazard Analysis and Critical Control Points (HACCP), Failure Mode Effects Analysis (FMEA) and the Reduction of Human Error can provide the formal basis for such analyses; and
  3. Experience with the proposed or similar product (and container closure system) and proposed or similar sterilization process, the overall risks to sterility, and the steps taken to assess and control these risks. For new products, prior knowledge from developmental and registration/exhibit batches may suffice.

 

C. Documentation: Following information specific to the proposed parametric release process shall be submitted for approval:

  1. A citation to a complete and detailed description of the current relevant terminal sterilization cycle;
  2. Identification of the critical process parameters (process/cycle parameters and appropriate load monitors essential for product release) for the product(s) proposed for parametric release, including the minimum and maximum limits for these critical parameters. The critical process parameters should be within the limits that have been validated and approved for sterility assurance of the subject product(s);
  3. Acknowledgement that adherence to the critical parameters of the parametric release program will substitute for the performance of a sterility test as the primary release criterion for the product and that sterility test results from the finished product will not be used to overrule any failure to meet the acceptance criteria of the parametric release program. In the event of failure, the specific sterilizer load will be rejected by the quality control unit and will not be released unless there is a provision for reprocessing;
  4. Acknowledgement that regardless of the batch release technique used, any specimen tested according to the reference test method for sterility (e.g., IP/BP/USP/EP/FP/JP/CP etc.) will meet the criteria for sterility;
  5. A description of the sterilization load monitor shall indicate the type of monitor being proposed, use and analysis of the load monitor, functions being measured by the monitor, and the rationale for the location of the monitor;
  6. Documentation of the control system to verify exposure of the load to the sterilization process; and
  7. Revision of the certificates of analysis or batch release records for each product.

The personnel carrying out or involved in parametric release shall be suitably trained. The team must include a sterility assurance engineer with knowledge of automated systems, if applicable, and a microbiologist. The number of people involved should be sufficient to cover normal absenteeism.

 

Release Procedure: A quality assurance program shall be established that describes in detail the batch or lot release steps for parametric release of sterilized products and the required documentation. Apart from the measurement of physical process parameters, review of batch records; review of the ongoing microbiological environmental control program results and pre-sterilization bioburden; and a review of records of thermographic data, load monitors, and results of critical and noncritical data that may have been used to demonstrate process control shall be carried out. Calibration, Maintenance, Validation status of the sterilizer shall be ensured.

Challenges associated with Parametric Release:

  1. Sterilization load monitors: Load monitors are considered as a critical process parameter. Results of the sterilization load monitor(s) satisfies the requirement for a laboratory test for sterility as required by 21 CFR 211.167(a) to allow commercial release of a drug product. Additionally, the load monitor(s) provides evidence that the load has been exposed to sterilization.
  2. Production experience/ historical data: Manufacturing experience related to carrying out of terminal sterilization and release of product based on the results of a sterility test for a period of time.

 

Can we release a batch if it fails to meet parametric release parameters but passes the sterility test? The implementation and practice of parametric release is not an intermittent program. Once such a program is implemented, release of the sterilized product is made in accordance with the requirements of the regulatory approved program. Product release by other means is not acceptable if the predefined critical operational parameters are not achieved.

 

Parametric release of other drug products: The results of a comprehensive set of in-process tests and controls may constitute sufficient grounds for batch release and provide greater assurance of the finished product meeting certain criteria in the specification without the tests being repeated on a sample of the finished product. Process monitoring may be applied to other manufacturing processes, such as tabletting, on the basis of manufacturing history and appropriate testing at various stages in the process. Some parameters are usually checked routinely at defined intervals regardless of the design of the manufacturing process of a tablet. Examples from tablet manufacture could be in-process testing of uniformity of mass, hardness, friability and disintegration. Other examples are the use of process analytical chemistry test methods, such as near-infrared spectrometry (NIR) and Raman spectroscopy, by which in line monitoring particle size, content of active substance, homogeneity, water content or film thickness can be achieved.

 

Additional facts:

  • The European Pharmacopoeia refers to parametric release without making a distinction between human and veterinary medicinal products,
  • FDA has accepted the practice of parametric release for drug products terminally sterilized by moist heat since 1985.
  • Parametric release and sterilisation Parametric release is referred to in the monograph ”Methods of preparation of sterile products” in the European Pharmacopoeia.

 

Parametric release holds its importance in optimizing the resources available with a pharmaceutical manufacturer and provides quicker access of the drug to the patients. However, one has to be very confident about the systems in-place, their controls, validations, experience and training of personnel involved, risk assessment, critical process parameters (CPP), critical quality attributes (CQA) before the decision to go ahead with the filing for approval of parametric release is taken. Due regulatory approval shall also be taken before implementing parametric release.

 

References:

  1. “Terminally Sterilized Pharmaceutical Products—Parametric Release” Chapter 1222, USP 32
  2. Guidance for Industry – Submission of Documentation in Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes
  3. PIC/S – Guidance on Parametric Release
  4. EMEA – Guidelines on Parametric Release
  5. Parametric Release – A Regulatory Perspective by Dr. Marla Stevens-Riley